Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 809–816

The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature

  • Shu Zhao
  • Yupeng Liu
  • Qingyuan Zhang
  • Hongbin Li
  • Minghui Zhang
  • Wenjie Ma
  • Wenhui Zhao
  • Jingxuan Wang
  • Maopeng Yang
Preclinical study


The prognostic significance of circulating tumor cells (CTCs) in patients with breast cancer is controversial. We performed a meta-analysis of published literature to assess whether the detection of CTCs in patients diagnosed with primary breast cancer can be used as a prognostic factor. We searched Medline, Science Citation Index, and Embase databases as well as reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB). A total of 24 eligible studies with 4,013 cases and 1,333 controls were included. Meta-analyses were performed using a random-effects model, using the hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. The positive detection of CTCs in patients was significantly associated with poor overall survival (OS) (HR = 3.00 [95% CI 2.29–3.94], n = 17, P < 0.0001) and recurrence-free survival (RFS) (HR = 2.67 [95% CI 2.09–3.42], n = 22, P < 0.0001). CTC-positive breast cancers were significantly associated with high histological grade (HR = 1.21 [95% CI 1.09–1.35], n = 34, P < 0.0001), tumor size (>2 cm) (HR = 1.12 [95% CI 1.02–1.22], n = 31, P = 0.01). and nodal status (≥1) (HR = 1.10 [95% CI 1.00–1.21], n = 32, P = 0.037), but cytokeratin-19 (CK-19) mRNA-positive CTCs were not associated with these clinicopathological parameters of breast cancer. Furthermore, the presence of CTCs was not associated with estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, or human epidermal growth factor receptor type 2 (HER2) positivity. Detection of CTCs in the PB indicates poor prognosis in patients with primary breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice.


Circulating tumor cells Breast cancer Prognosis RT-PCR 

Supplementary material

10549_2011_1379_MOESM1_ESM.doc (130 kb)
Supplementary material 1 (DOC 130 kb)


  1. 1.
    Jemal A, Siegel S, Ward E, Thun MJ et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249Google Scholar
  2. 2.
    Ashworth TR (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J 14:146–149Google Scholar
  3. 3.
    Van der Auwera I, Peeters D, Benoy IH et al (2010) Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer. Br J Cancer 102:276–284PubMedCrossRefGoogle Scholar
  4. 4.
    Kahn HarrietteJ, Yang Lu-Ying, Blondal John et al (2000) RT-PCR amplification of CK19 mRNA in the blood of breast cancer patients: correlation with established prognostic parameters. Breast Cancer Res Treat 60:143–151PubMedCrossRefGoogle Scholar
  5. 5.
    Stathopoulou A, Vlachonikolis I, Mavroudis D et al (2002) Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol 20:3404–3412PubMedCrossRefGoogle Scholar
  6. 6.
    Xenidis N, Vlachonikolis I, Mavroudis D et al (2003) Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer. Ann Oncol 14:849–855PubMedCrossRefGoogle Scholar
  7. 7.
    Jotsuka T, Okumura Y, Nakano S et al (2004) Persistent evidence of circulating tumor cells detected by means of RT-PCR for CEA mRNA predicts early relapse: a prospective study in node-negative breast cancer. Surgery 135:419–426PubMedCrossRefGoogle Scholar
  8. 8.
    Ntoulia M, Stathopoulou A, Ignatiadis M et al (2006) Detection of mammaglobin A-mRNA-positive circulating tumor cells in peripheral blood of patients with operable breast cancer with nested RT-PCR. Clin Biochem 39:879–887PubMedCrossRefGoogle Scholar
  9. 9.
    Chen C-C, Chang T-W, Chen F-M et al (2006) Combination of multiple mRNA markers (PTTG1, Survivin, UbcH10 and TK1) in the diagnosis of Taiwanese patients with breast cancer by membrane array. Oncology 70:438–446PubMedCrossRefGoogle Scholar
  10. 10.
    Xenidis N, Perraki M, Kafousi M et al (2006) Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients. J Clin Oncol 24:3756–3762PubMedCrossRefGoogle Scholar
  11. 11.
    Xenidis N, Markos V, Apostolaki S et al (2007) Clinical relevance of circulating CK-19 mRNA-positive cells detected during the adjuvant tamoxifen treatment in patients with early breast cancer. Ann Oncol 18:1623–1631PubMedCrossRefGoogle Scholar
  12. 12.
    Ignatiadis M, Xenidis N, Perraki M et al (2007) Different prognostic value of cytokeratin-19 mRNA-positive circulating tumor cells according to estrogen receptor andHER2 status in early-stage breast cancer. J Clin Oncol 25:5194–5202PubMedCrossRefGoogle Scholar
  13. 13.
    Ignatiadis M, Perraki M, Apostolaki S et al (2007) Molecular detection and prognostic value of circulating cytokeratin-19 messenger RNA-positive and HER2 messenger RNA-positive cells in the peripheral blood of women with early-stage breast cancer. Clin Breast Cancer 7:883–889PubMedCrossRefGoogle Scholar
  14. 14.
    Ignatiadis M, Kallergi G, Ntoulia M et al (2008) Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer. Clin Cancer Res 14:2593–2600PubMedCrossRefGoogle Scholar
  15. 15.
    Apostolaki S, Perraki M, Kallergi G et al (2009) Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance. Breast Cancer Res Treat 117:525–534PubMedCrossRefGoogle Scholar
  16. 16.
    Xenidis N, Ignatiadis M, Apostolaki S et al (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol 27:2177–2184PubMedCrossRefGoogle Scholar
  17. 17.
    Chen Y, Zou TN, Wu ZP et al (2010) Detection of cytokeratin 19, human mammaglobin, and carcinoembryonic antigen-positive circulating tumor cells by three-marker reverse transcription-PCR assay and its relation to clinical outcome in early breast cancer. Int J Biol Markers 25:59–68PubMedGoogle Scholar
  18. 18.
    Suchy B, Austrup F, Driesel G et al (2000) Detection of mammaglobin expressing cells in blood of breast cancer patients. Cancer Lett 158:171–178PubMedCrossRefGoogle Scholar
  19. 19.
    Lin Y-C, Chen S-C, Hsueh S et al (2003) Lack of correlation between expression of human mammaglobin mRNA in peripheral blood and known prognostic factors for breast cancer patients. Cancer Sci 94:99–102PubMedCrossRefGoogle Scholar
  20. 20.
    Benoy IH, Elst H, Philips M et al (2006) Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 13:672–680Google Scholar
  21. 21.
    Marques AR, Teixeira E, Diamond J et al (2009) Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence. Breast Cancer Res Treat 114:223–232PubMedCrossRefGoogle Scholar
  22. 22.
    Daskalaki A, Agelaki S, Perraki M et al (2009) Detection of cytokeratin-19 mRNA-positive cells in the peripheral blood and bone marrow of patients with operable breast cancer. Br J Cancer 101:589–597PubMedCrossRefGoogle Scholar
  23. 23.
    Ferro P, Franceschini MC, Bacigalupo B et al (2010) Detection of circulating tumour cells in breast cancer patients using human mammaglobin RT-PCR: association with clinical prognostic factors. Anticancer Res 30:2377–2382Google Scholar
  24. 24.
    Grünewald K, Haun M, Urbanek M et al (2000) Mammaglobin gene expression: a superior marker of breast cancer cells in peripheral blood in comparison to epidermal-growth-factor receptor and cytokeratin-19. Lab Invest 80:1071–1077PubMedCrossRefGoogle Scholar
  25. 25.
    Mikhitarian K, Martin RH, Ruppelet MB et al (2008) Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: interim results of a prospective cohort study. BMC Cancer 8:55–66PubMedCrossRefGoogle Scholar
  26. 26.
    Shen CX, Hu LH, Xia L et al (2009) The detection of circulating tumor cells of breast cancer patients by using multimarker (Survivin, hTERT and hMAM) quantitative real-time PCR. Clin Biochem 42:194–200PubMedCrossRefGoogle Scholar
  27. 27.
    Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802PubMedCrossRefGoogle Scholar
  28. 28.
    Theodoropoulos PA, Polioudaki H, Agelaki S et al (2010) Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett 288:99–106PubMedCrossRefGoogle Scholar
  29. 29.
    Watson MA, Fleming TP (1996) Mammaglobin, a mammaryspecific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865PubMedGoogle Scholar
  30. 30.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456PubMedCrossRefGoogle Scholar
  31. 31.
    Zlotnik A (2004) Chemokines in neoplastic progression. Semin Cancer Biol 14:181–185PubMedCrossRefGoogle Scholar
  32. 32.
    Brandt B, Roetger A, Heidl S et al (1998) Isolation of bloodbored epithelium-derived c-erb-B2 oncoprotein-positive clustered cells from the peripheral blood of breast cancer patients. Int J Cancer 76:824–828PubMedCrossRefGoogle Scholar
  33. 33.
    Wulfing P, Brochard J, Buerger H et al (2006) HER2 positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res 12:1715–1720PubMedCrossRefGoogle Scholar
  34. 34.
    Bozionellou V, Mavroudis D, Perraki M et al (2004) Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clin Cancer Res 10:8185–8194PubMedCrossRefGoogle Scholar
  35. 35.
    Meng S, Tripathy D, Shete S et al (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 10:9393–9398CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Shu Zhao
    • 1
  • Yupeng Liu
    • 2
  • Qingyuan Zhang
    • 1
  • Hongbin Li
    • 1
  • Minghui Zhang
    • 1
  • Wenjie Ma
    • 1
  • Wenhui Zhao
    • 1
  • Jingxuan Wang
    • 1
  • Maopeng Yang
    • 1
  1. 1.Department of Internal MedicineThe Third Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of EpidemiologyPublic Health College of Harbin Medical UniversityHarbinChina

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